PROJECT SUMMARY Human physiology and disease pathobiology are a manifestation of underlying genetic predisposition interacting with superimposed environmental exposures. Whereas genetic factors are generally stable from conception, environmental exposures are dynamic over the lifespan, and ultimately account for up to 90% of population-attributable risk for human disease, including for cardiovascular disease, the number cause of mortality in the developed world. The totality of environmental exposures, or the ?exposome?, represents the aggregate of both internal exposures originating from host state/physiology and host microbiota, as well as external exposures deriving from toxicants and chemicals, aerosolized particulate matter and pollution, infectious agents, as well as diet and drugs. These environmental exposures result in the introduction of small molecules into human circulation where they may be monitored as biomarker surrogates of specific exposures even years or decades prior to onset of overt disease. To date, targeted approaches have begun to detail the small molecules that comprise the plasma exposome in humans. Still lacking, however, is a global view of the thousands of known and yet undiscovered small molecules that comprise the human exposome on a population level scale and rigorous association of these small molecules with the prospective development of human disease. The fundamental barrier in our understanding of the exposome and its role in human disease remains the lack of advanced analytical approaches that enable the simultaneous and rapid measure of the thousands of small molecules that comprise the plasma exposome on a population level scale. In this NIEHS Outstanding New Environmental Scientist (ONES) Award, it is our central goal to comprehensively map the human plasma exposome, understand its dynamic nature over time, and determine its role in human cardiovascular disease. To do so, we will apply novel, high throughput mass spectrometry based approaches to measure the thousands of environmentally derived small molecules present in human plasma. In serial plasma samples obtained over time from 1000 healthy individuals we will determine the natural variation in the exposome from individual to individual and over time in a single individual, the components of the exposome attributable to specific environmental exposures, and the relationship between the exposome and over forty baseline clinical demographics. Additionally, in two independent, large scale prospective epidemiological cohorts, we will determine the association between specific exposome related small molecules, interaction with disease associated genetic variants, and the prospective development of cardiovascular disease years in advance. This NIEHS ONES award will provide support for a uniquely poised Early State Investigator with diverse expertise in mass spectrometry based analytics, environmental epidemiology, computational sciences, cardiovascular biomedicine and a history of high impact biological discovery, as well as provide a foundation from which to launch an innovative, long-term research program committed to the study of environmental health sciences. !